Allogeneic gamma delta T cells as adoptive cellular therapy for hematologic malignancies

Abstract

Cancer immunotherapy, especially T-cell driven targeting, has significantly evolved and improved over the past decade, paving the way to treat previously refractory cancers. Hematologic malignancies, given their direct tumor accessibility and less immunosuppressive microenvironment compared to solid tumors, are better suited to be targeted by cellular immunotherapies. Gamma delta (γδ) T cells, with their unique attributes spanning the entirety of the immune system, make a tantalizing therapeutic platform for cancer immunotherapy. Their inherent anti-tumor properties, ability to act like antigen-presenting cells, and the advantage of having no major histocompatibility complex (MHC) restrictions, allow for greater flexibility in their utility to target tumors, compared to their αβ T cell counterpart. Their MHC-independent anti-tumor activity, coupled with their ability to be easily expanded from peripheral blood, enhance their potential to be used as an allogeneic product. In this review, the potential of utilizing γδ T cells to target hematologic malignancies is described, with a specific focus on their applicability as an allogeneic adoptive cellular therapy product.

Keywords: Gamma delta T cells; allogeneic; chimeric antigen receptor; immunotherapy; leukemia.

Figure 1.

γδ T cell-mediated cytotoxicity against tumor cells. γδ T cells have several direct cytotoxic mechanisms against tumor cells as shown above. Binding of the phosphoantigen to the γδ TCR triggers activation resulting in target cell lysis and also stimulates the release of TNF-α and IFN-γ, which enhances the anti-tumor activity of other immune cells. Additional cytotoxic mechanisms include ADCC through CD16 expression, NKG2D and DNAM-1 receptor-ligand interactions as well as the activation of the TRAIL-TRAIL receptor and Fas ligand (FasL)-Fas receptor pathway